Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-14
2004-02-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S263360, C514S263380, C514S369000
Reexamination Certificate
active
06693106
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to the modification and aging of proteins through reaction with glucose and other reducing sugars, such as fructose or ribose and more particularly to the inhibition of nonenzymatic glycation of proteins which often results in formation of advanced glycation endproducts and crosslinks.
An elevated concentration of reducing sugars in the blood and in the intracellular environment results in the nonenzymatic formation of glycation and dehydration condensation complexes known as advanced glycation end-products (AGE's). These complex products form on free amino groups on proteins, on lipids and on DNA (Bucala and Cerami, 1992; Bucala et al., 1993; Bucala et al., 1984). This phenomenon is called “browning” or “Maillard” reaction and was discovered early in this century by the food industry (Maillard, 1916). The significance of a similar process in biology became evident only after the discovery of the glycosylated hemoglobins and their increased presence in diabetic patients (Rahbar, 1968; Rahbar et al., 1969). In human diabetic patients and in animal models of diabetes, these nonenzymatic reactions are accelerated and cause increased AGE formation and increased glycation of long-lived proteins such as collagen, fibronectin, tubulin, lens crystallin, myelin, laminin and actin, in addition to hemoglobin and albumin, and also of LDL associated lipids and apoprotein. Moreover, brown pigments with spectral and fluorescent properties similar to those of late-stage Maillard products have also been found in vivo in association with several long-lived proteins such as lens crystallin proteins and collagen from aged individuals. An age-related linear increase in pigments was observed in human dura collagen between the ages of 20 to 90 years. AGE modified proteins increase slowly with aging and are thought to contripbute to normal tissue remodeling. Their level increases markedly in diabetic patients as a result of sustained high blood sugar levels and lead to tissue damage through a variety of mechanisms including alteration of tissue protein structure and function, stimulation of cellular responses through AGE specific receptors or the generation of reactive oxygen species (ROS) (for a recent review see Boel et al., 1995). The structural and functional integrity of the affected molecules, which often have major roles in cellular functions, become perturbed by these modifications, with severe consequences on affected organs such as kidney, eye, nerve, and micro-vascular functions (Silbiger et al., 1993; Brownlee et al., 1985).
Structural changes on macromolecules by AGE's are known to accumulate under normal circumstances with increasing age. This accumulation is severely accelerated by diabetes and is strongly associated with hyperglycemia. For example, formation of AGE on protein in the subendothelial basement membrane causes extensive cross-link formation which leads to severe structural and functional changes in protein/protein and protein/cell interaction in the vascular wall (Haitoglou et al., 1992; Airaksinen et al., 1993).
Enhanced formation and accumulation of advanced glycation end products (AGE's) have been proposed to play a major role in the pathogenesis of diabetic complications and in aging, leading to progressive and irreversible intermolecular protein crosslinkings (Monnier et al., 1986). This process is accelerated by diabetes and has been postulated to contribute to the development of a range of diabetic complications including nephropathy (Nicholls and Mandel, 1989), retinopathy (Hammes et al., 1991) and neuropathy (Cameron et al., 1992). Particularly, tissue damage to the kidney by AGE's leads to progressive decline in renal function and end-stage renal disease (ESRD) (Makita et al., 1994), and accumulation of low-molecular-weight (LMW) AGE peptides (glycotoxins) (Koschinsky et al., 1997) in the serum of patients with ESRD (Makita et al., 1991). These low molecular weight (LMW)-AGE's can readily form new crosslinks with plasma or tissue components, e.g., low density lipoprotein (LDL) (Bucala et al., 1994) or collagen (Miyata et al., 1993) and accelerate the progression of tissue damage and morbidity in diabetics.
The Diabetic Control and Complications Trial (DCCT), has identified hyperglycemia as the main risk-factor for the development of diabetic complications (The Diabetes Control and Complications Trial Research Group, 1993). Although there is no consensus regarding the pathogenic link between hyperglycemia and diabetic complications, formation of advanced glycation endproducts (AGE's) has been implicated as a major pathogenic process in the long-term complications of diabetes, namely nephropathy, neuropathy and retinopathy.
Particularly, tissue damage to the kidney by AGE's leads to progressive decline in renal function and end-stage renal failure (ESRD) (Makita et al., 1994), and accumulation of low-molecular-weight (LMW) AGE peptides (glycotoxins) (Koschinsky et al., 1997) in the serum of patients with ESRD (Makita et al., 1991). These low molecular weight (LMW)-AGE's can readily form new cross-links with plasma or tissue components, e.g., low density lipoprotein (LDL) (Bucala et al., 1994) or collagen (Baily et al., 1998) and accelerate the progression of tissue damage and morbidity in diabetes.
Although the mechanism of non-enzymatic glycation is not completely understood and the precise structures of major AGE components remain to be established, &agr;-dicarbonyl compounds have been identified as major intermediates in the glycation pathways and cross-linking of proteins by glucose (Baynes and Thorpe, 1999). Hyperglycemia is associated with the formation of dicarbonyl compounds, particularly methylglyoxal (MGO), glyoxal (GO), 3-deoxyglucosone (3-DG), glycoaldehyde and dehydroascorbate (Onorato et al., 1998). In patients with both insulin-dependent and non-insulin dependent diabetes, the concentration of MGO was found to be increased 2-6-fold (McLellan et al., 1994). The major source of MGO is thought to be the non-enzymatic dephosphorylation of the triosedihydroxyacetone phosphate and glyceraldehyde-3-phosphate. In addition, glucose auto-oxidation and degradation of Amadori products and enzymatic catabolism of acetone through the acetol pathway (Phillips and Thornalley, 1993) are alternative sources of MGO formation. The glyoxylase system (I and II) and aldose reductase catalyze the detoxification of MGO to D-lactate. MGO binds to and irreversibly modifies arginine and lysine residues in proteins. MGO modified proteins have been shown to be ligands for the AGE receptor (Beisswenger et al., 1998), indicating that MGO modified proteins are analogous (Beisswenger et al., 1998) to those found in AGE's. Most recently, the effects of MGO on LDL has been characterized in vivo and in vitro (Westwood et al., 1997).
Lipid peroxidation of polyunsaturated fatty acids (PUFA), such as arachidonate, also yield carbonyl compounds; some are identical to those formed from carbohydrates (Schalkwijk et al., 1998), such as MGO and GO, and others are characteristic of lipid, such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) (Bucala et al., 1993). The latter carbonyl compounds produce lipoxidation products, such as MDA-lysine, lysine-MDA-lysine, HNE-protein adducts (HNE Lys, His, Cys) (Al-Abed et al., 1996). AGE compounds characterized in vitro and in vivo are either the result of glycation alone or glycation-oxidation modification called glycoxidation products. Glycoxidation products that have been detected in tissue proteins are N
&egr;
-carboxymethyl-lysine (CML), N
&egr;
-carboxyethyl-lysine (CEL), N
&egr;
-carboxymethyl-ethanolamine (CME) (Requena et al., 1997), pentosidine, glyoxal-lysine-dimer (GOLD) and methylglyoxal-lysine-dimer (MOLD). These products may be derived from either glycoxidation or lipoxidation reactions. Other AGE's detected in tissue proteins are pyrraline, crossline imidazolium salts formed by the reaction of MOLD or GOLD and imidazol
Nadler Jerry L.
Rahbar Samuel
City of Hope
Krass Frederick
LandOfFree
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